Network wide analysis of brain activity involved in alcohol withdrawal

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Project Summary / Abstract Alcohol use disorder (AUD) is one of the leading causes of preventable death in the United States. AUD is a chronic relapsing disorder that is associated with loss of control and compulsive drinking. The emergence of negative emotional states during acute withdrawal and their maintenance during protracted abstinence are critical driving forces that lead to excessive and compulsive-like alcohol drinking. Identifying the neurocircuitry that is involved in negative emotional states and excessive alcohol drinking is a critical step to understanding the neuronal causes of compulsive alcohol drinking. We have already identified several key brain regions that are recruited during acute alcohol withdrawal, but still unknown is whether these circuits are different during protracted abstinence. Additionally, previous research has often been biased by the preselection of regions of interest; therefore, unbiased whole-brain functional circuitry imaging is a critical step to examine the entire brain and identify entire networks that are involved in alcohol withdrawal. I will utilize the whole-brain imaging of immediate early genes to identify brain regions that are recruited during acute alcohol withdrawal and protracted abstinence. Once these brain regions are identified, they will be compared with regard to functional relationships using correlational analyses and graph theory. These analyses will identify critical components (brain regions) of the functional network of acute alcohol withdrawal and protracted abstinence. These critical components or hubs, once identified, will be targeted and selectively inactivated using the Daun02/LacZ approach to test causal relationships between these hubs and negative emotional states and compulsive alcohol drinking in dependent mice. These studies will be started at The Scripps Research Institute during my K99 phase and completed at my future institution during my independent R00 phase. During my K99 phase, I will receive training in graph theory analyses and Daun02 inactivation to identify and disrupt critical nodes within the functional network of alcohol abstinence. During the R00 phase, I will use Daun02 inactivation to continue these projects and further explore the ways in which the disruption of critical nodes within the functional alcohol abstinence network changes alcohol-related behavior. Collectively, this work will provide insights into the functional circuitry that contributes to alcohol addiction, reveal novel targets and testable hypotheses for future brain imaging studies in human, and facilitate the development of novel treatments for AUD, including targets for noninvasive brain stimulation.